Zou Jianling, Yang Wentao, Li Shuang, Liu Fei, Chang Jinjia, Li Wenhua, Huang Mingzhu, Zhu Xiaodong, Zou Jianyin, Guo Weijian, Chen Zhiyu
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Cancer Med. 2025 Jul;14(14):e71061. doi: 10.1002/cam4.71061.
Cytotoxic agents remain the mainstay treatment for advanced gastrointestinal cancer. However, the number of cytotoxic agents is limited, and the treatment effect is not satisfactory. Therefore, new agent and combination strategies are to be explored.
The antitumor efficacy of low-dose epigenetic modifiers (LD-EMs) of 5-azacytidine and entinostat, cytotoxic agents of paclitaxel, cisplatin, oxaliplatin, 5-fluorouracil, and a novel cytotoxic agent TIC10, and the combination of LD-EMs and cytotoxic agents was investigated in vivo. Flow cytometry and immunohistochemistry were conducted to analyze the immune phenotype in the tumor microenvironment. The proliferation and apoptosis analyses were performed in vitro.
LD-EM therapy demonstrated superior tumor inhibition compared with commonly used chemotherapy in gastrointestinal cancer. A novel cytotoxic agent TIC10 resulted in weak to moderate tumor growth inhibition (TGI). LD-EMs exhibited a more pronounced antitumor effect than TIC10 alone (CT26: TGI of 74.5% vs. 46.2%, respectively; p < 0.05; HNM007: TGI of 52.0% vs. 21.4%, respectively; p < 0.05; AKR: TGI of 53.8% vs. 10.1%, respectively; p < 0.05). The combination of TIC10 and LD-EMs led to a more pronounced tumor reduction with tolerable toxicity. Analysis of the immune profiles showed increased percentages of CD45 lymphocytes, CD3 and CD8+ T cells, M1 macrophages, and dendritic cells, whereas decreased percentages of M2 macrophages and myeloid-derived suppressor cells under treatment with LD-EMs and combination therapy. Mechanistic studies revealed that LD-EMs activated the RIG-I-MAVS pathway, stimulated type I interferon responses, and subsequently promoted chemokine secretion. In contrast, TIC10 suppressed cell viability and induced cell apoptosis.
LD-EMs remodeled the tumor microenvironment to an immune-promoting environment. Although TIC10 could suppress cell viability and induce cell apoptosis. A combination of LD-EMs and TIC10 indicated a rational strategy through complementary mechanisms.
细胞毒性药物仍然是晚期胃肠道癌的主要治疗方法。然而，细胞毒性药物的数量有限，治疗效果并不令人满意。因此，需要探索新的药物和联合治疗策略。
研究了低剂量表观遗传修饰剂（LD-EMs）5-氮杂胞苷和恩替诺特、细胞毒性药物紫杉醇、顺铂、奥沙利铂、5-氟尿嘧啶以及新型细胞毒性药物TIC10的体内抗肿瘤疗效，以及LD-EMs与细胞毒性药物的联合疗效。采用流式细胞术和免疫组织化学分析肿瘤微环境中的免疫表型。在体外进行增殖和凋亡分析。
与常用的胃肠道癌化疗相比，LD-EM治疗显示出更好的肿瘤抑制作用。新型细胞毒性药物TIC10导致轻度至中度的肿瘤生长抑制（TGI）。LD-EMs单独使用比TIC10表现出更显著的抗肿瘤作用（CT26：TGI分别为74.5%和46.2%；p<0.05；HNM007：TGI分别为52.0%和21.4%；p<0.05；AKR：TGI分别为53.8%和10.1%；p<0.05）。TIC10与LD-EMs联合使用导致更显著的肿瘤缩小且毒性可耐受。免疫谱分析显示，在LD-EMs和联合治疗下，CD45淋巴细胞、CD3和CD8+T细胞、M1巨噬细胞和树突状细胞的百分比增加，而M2巨噬细胞和髓源性抑制细胞的百分比降低。机制研究表明，LD-EMs激活RIG-I-MAVS通路，刺激I型干扰素反应，随后促进趋化因子分泌。相反，TIC10抑制细胞活力并诱导细胞凋亡。
LD-EMs将肿瘤微环境重塑为免疫促进环境。虽然TIC10可以抑制细胞活力并诱导细胞凋亡。LD-EMs与TIC10联合使用通过互补机制显示出一种合理的策略。
